Structure-function Analysis of E-cadherin Dimerization at the Plasma Membrane

Abstract

This study identified a critical region of E-cadherin that both drives the formation of lateral dimers at the plasma membrane and affects intercellular junction assembly and function. Cadherin oligomers are fundamental building blocks of intercellular junctions. Prior findings indicate that cadherin oligomerization regulates tissue cohesion and paracellular permeability. Current models of cadherin dimerization/oligomerization focus on the cis-interactions between the extracellular domains. These studies used novel FullSpectral Imaging Förster Resonance Energy Transfer (FSI-FRET) technique to directly quantify binding interactions or E-cadherin and its mutants, to identify protein regions required for homodimerization at the plasma membrane. Although the extracellular region contributes modestly to the dimerization propensity, FSI-FRET results demonstrated that the intracellular domain is the major contributer to E-cadherin dimerization. The intracellular region is crucial for both lateral dimerization and the formation of large cadherin clusters at cell-cell adhesions. In studies of cadherin mutants that lack this domain, actin anchoring did not rescue clustering. Destabilizing E-cadherin dimers through domain deletions sharply impaired the ability of E-cadherins to cluster and increased epithelial monolayer permeability. Further structure-function analysis explored the mechanism by which the intracellular domain modulates E-cadherin dimerization.